tbuckley/cabot-search huggingface dataset:
EPID-18. THE GENOMIC ARCHITECTURE OF GLIOBLASTOMA PREDISPOSITION IS HIGHLY POLYGENIC IN PATIENTS WITH A POSITIVE FAMILY HISTORY OF GLIOMA
Authors: Kyle Walsh, Quinn Ostrom, Jinyoung Byun, Courtney Wimberly, Georgina Armstrong, Christopher Amos, Melissa Bondy
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Genetic predisposition to glioblastoma (GBM) is highly polygenic and typically reflects the additive contributions of many common polymorphisms. However, patients with a positive family history of glioma may have a monogenic cancer predisposition syndrome. Such patients would be expected to have reduced contributions from common risk alleles. METHODS We sought to compare the polygenic risk of GBM among patients with a confirmed family history of glioma to those with a negative family history. Study subjects included 1628 GBM patients from the GICC study, who completed detailed questionnaires regarding personal and family medical history and underwent genome-wide genotyping of blood-derived DNA on the Illumina OncoArray. Polygenic risk scores were generated based on the 17 independent hits discovered by genome-wide association study (GWAS), with variants weighted by their respective effect sizes. RESULTS As expected, polygenic risk scores were significantly higher in GBM patients than in cancer-free control subjects (P=6.6x10-57). A total of 78 GBM patients had a positive family history of glioma, validated by record review. Across strata of family history, we observed that GBM patients with a positive family history of glioma had higher polygenic scores than patients with a negative family history (P=0.039). These results were robust in sensitivity analyses, where each of the 17 contributing variants were excluded from the model, one at a time. CONCLUSIONS Polygenic risk scores for GBM are significantly higher in patients with a positive family history of glioma. This suggests that, while family history can be due to rare, penetrant alleles, a large contingent of familial GBM may arise in families with a heavy polygenic burden of GBM risk alleles. Strategies for rare variant discovery might consider a two-pronged approach of sequencing kindreds with multiple affected members, as well as solitary GBM diagnoses in patients that have low polygenic risk scores.
QLTI-06. EVALUATING TWO DECADES OF GLIOBLASTOMA CARE IN THE UNITED STATES VETERANS HEALTH ADMINISTRATION
Authors: Margaret O Johnson, Chin-Lin Tseng, Kerry Rowe, Vida A Passero, Michael J Kelley, Sara T Ahmed, Michael A Mooney
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The Veterans Health Administration (VHA) provides healthcare for U.S. military Veterans, including specialized care for glioblastoma (GBM). This study aimed to understand patterns of care and outcomes for Veterans with GBM. METHODS We derived a retrospective cohort of U.S. Veterans with histological diagnosis of GBM in 2000-2021 from the VHA cancer registry system (CRS), with follow-up times through May 31, 2022. Data sources were patient-level electronic health records, CRS, and other data from the VHA corporate data warehouse. Using descriptive statistics, we describe demographics, treatments, clinical outcomes, referral patterns, and overall survival (OS). RESULTS We identified 3,802 Veterans with GBM (median per year = 176, range 76-225). Among the 465 veterans diagnosed in 2018-2021, 192 (41%) had unknown IDH mutational status. The median age at diagnosis was 66 years (range 20-101), most were male (97%), non-Hispanic (78%) and white (70%). 32% were considered rural and 2% highly rural. 71% received radiation and 61% (n = 2,301) received systemic therapy with the most common being temozolomide (96%), bevacizumab (16%), and lomustine (6%). First use of Novo-TTF was February 2020 with a total of 25 total users to-date. Between 2018-2021, 57% (range 54-63%) of veterans received cancer-related community referrals (i.e. medical oncology, radiation oncology, or neurosurgery). The yearly rate of palliative care referrals remained ≥40% since 2008 and was highest in 2021 (64%). Median OS was 6.9 months (95% CI:6.6-7.3). CONCLUSIONS Using the largest cohort of Veterans with GBM, we identified gaps in molecular testing data and note a large fraction that received community care referrals. Patterns of cancer-directed therapy appear consistent with best practices, although the unadjusted median OS for Veterans was shorter than reported in other populations. In response to these findings, VHA is developing strategies to improve access, quality and research for Veterans with GBM.
NIMG-01. AI-BASED ASSESSMENT OF BRAIN VOLUME DECREASE AFTER SRS AND WBRT
Authors: Frederic Thiele, Maria Kawula, Sophie Katzendobler, Raphael Bodensohn, Christopher Kurz, Guillaum Landry, Jonathan Weller, Maximilian Niyazi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Stereotactic radiosurgery (SRS) for 4-10 brain metastases has been shown to be associated with prolonged survival as compared to whole brain radiotherapy (WBRT). Brain volume decrease after WBRT is a marker for poor survival. We aimed at comparing brain volume decrease in patients treated with either SRS or WBRT. METHODS Patients treated with SRS were drawn from the prospective dataset of the STEREOBRAIN study (DRKS00014694) that recruited from 2017 to 2020. Patients that received WBRT for 4-10 brain metastases were included retrospectively from 2012 - 2017. Images were registered to the MNI305 space utilizing the Advanced Normalization Tools (ANTs) Toolkit. Brain extraction was performed using the deep-learning based HD-BET UNet. Anatomical brain structures were labelled by employing the current state-of-the-art pretrained transformer based UNesT network using the MONAI deep-learning framework. Labels were bundled and analysed. Last pre-radiotherapy scans were compared with the last post-radiotherapy scans. The proportion of the ventricular system to the total intracranial volume was implemented as a measure of brain volume decrease. RESULTS Overall, 65 patients were included. 29 patients (45%) received SRS and 36 patients (55%) were treated with WBRT. Patients treated with SRS showed no significant increase in the volume of the ventricular system compared to the total intracranial volume (p= 0.13), whereas patients in the WBRT cohort did (p&amp;lt; 0.01). The mean relative volume increase of the ventricular system was 33% in the SRS cohort. In the WBRT cohort, the mean increase was 54%. The median time between the two scans was 414 days in the SRS cohort and 244 days in the WBRT cohort. CONCLUSION Brain volume decrease is less extensive in patients treated with SRS than WBRT. The clinical implication of this finding, e.g., prolonged survival and better clinical status, is yet to be determined and quantified.
DDDR-13. ST-401, A BRAIN PENETRATING MICROTUBULE TARGETING AGENT THAT KILLS GLIOBLASTOMA IN INTERPHASE AND BY DISRUPTING MITOCHONDRIA FUNCTION
Authors: Kainat Khan, Dennis Sarroza, Juan Vicente, Linda Wordeman, Yasemin Sancak, Nephi Stella
Journal: Neuro-Oncology (2023)

Abstract The development of small molecular entities that can effectively penetrate the blood-brain barrier and kill glioblastoma (GBM) is crucial in Neuro-Oncology. ST-401, a unique microtubule depolymerizer, has shown remarkable potential as a therapeutic agent for GBM in PD-GBM isolates (nanomolar potencies) and in vivo preclinical GBM models (potencies DNA-damaging agents). This study aims to investigate the novel mechanism of action of ST-401 and its impact on GBM cell death. We recently showed that increasing concentrations of ST-401 disrupts mitochondrial function, leading to cell death initially in interphase and then in mitosis. Through single-cell RNA sequencing analysis, significant changes in mRNA related to mitochondrial functions were observed, including ribosomal proteins and OXPHOS genes. The study focuses on the role of mitochondria in GBM tumorigenesis and explores how ST-401 affects mitochondrial OXPHOS function. We identified three GBM cell lines (U251, SNB-19, and SF-539) with increasing vulnerability to ST-401, respectively, as measured by using WST-1, an index of mitochondria OXPHOS. Further investigation using the Seahorse platform demonstrated that SF-539 cells treated with ST-401 exhibited a loss of spare capacitance and significantly reduced mitochondrial function, including basal and maximal OXPHOS response, as well as ATP production. In conclusion, our results emphasize the existence of specific subtypes of GBM that show vulnerability or resistance to the antitumor effects of ST-401. Identifying these subtypes is crucial for advancing precision Neuro-Oncology and facilitating human trials. Our results also suggest that ST-401's inhibition of microtubule function and induction of cell death in interphase are associated with the loss of mitochondrial respiratory function. Given the limited treatment options for brain tumors and the challenges in delivering drugs across the blood-brain barrier, the development of brain-penetrant drugs like ST-401 holds great promise. Funded by NIH (CA244213 to NS and NS106924 to NS).
CCRG-02. DEVELOPMENTALLY PARTITIONED PROLIFERATIVE COMPARTMENTS IN GLIOBLASTOMA
Authors: Christopher Plaisier, Samantha O'Connor, Sonali Arora, Kevin Petrecca, Anoop Patel, Patrick Paddison
Journal: Neuro-Oncology (2023)

Abstract It is now well established from single-cell RNA-seq studies that glioblastoma (GBM) tumors are complex, maligned neuro-developmental ecosystems harboring diverse tumor cell types. Neoplastic cells can resemble astrocytes, neural progenitors, oligodendrocyte progenitor cells, mesenchymal cells, and radial glial cells that contribute to tumor growth and homeostasis in specific ways. However, GBM single-cell data sets have failed to produce general models for transitions in and out of specific developmental and proliferative states in tumors. One reason is that human GBM tumors do not neatly resolve into developmental hierarchies. Here we focused on modeling GBM tumor cellular heterogeneity by defining "proliferative compartments" in single-cell transcriptomic data derived from primary tumors and early passage tumorsphere cultures. Previously, we observed that each tumor cell entering S-phase has a unique developmental signature that can be leveraged to define broader partitioned proliferative compartments (PPCs) with distinct developmental gene expression and genomic alteration patterns. Thus, we extracted the S-phase cells from a tumor, defined the proliferative compartments in that tumor using de novo clustering, determined the marker genes for each compartment, and defined the broader PPCs across tumors by de novo clustering based on similarity in marker genes. From a cohort of six tumors we observed eight broader PPCs and found that tumors can contain as many as five PPCs or as few as two. Because tumor growth and recurrence both require cell proliferation, we propose that patient-specific PPCs represent the engines of GBM progression.
NIMG-40. SUPER T2-FLAIR MISMATCH SIGN AS PROGNOSTIC IMAGING BIOMARKER FOR NON-ENHANCED ASTROCYTOMA, IDH-MUTANT
Authors: Iori Ozono, Shumpei Onishi, Takeshi Takayasu, Ushio Yonezawa, Akira Taguchi, Novita Khairunissa, Fumiyuki Yamasaki, Nobutaka Horie
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The T2-FLAIR mismatch sign has been established as a highly specific diagnostic imaging biomarker for astrocytoma, IDH-mutant. However, prognostic imaging biomarker for this tumor has not been well established. METHODS We retrospectively reviewed 31 cases of non-enhanced astrocytoma, IDH-mutant, WHO grade 2 and 3 treated at our hospital. We defined “super T2-FLAIR mismatch sign” positivity as having a significantly strong low signal comparable to cerebrospinal fluid, rather than just a pale FLAIR low-signal tumor region as in regular T2-FLAIR mismatch. We evaluated the presence or absence of T2-FLAIR mismatch sign and super T2-FLAIR mismatch sign using preoperative MRI and statistically analyzed the progression-free survival (PFS) and overall survival (OS) using log-rank test. RESULTS The median age of this patient group was 40 (ranging 19-75) years, and consisted with 21 males and 10 females., with 21 males and 10 females. There were 25 cases of grade 2 and six cases of grade 3. T2-FLAIR mismatch sign was observed in 17 cases (54.8%) (grade 2: 16 cases, grade 3: 1 case), and super T2-FLAIR mismatch sign was observed in eight cases (25.8%) (grade 2: 8 cases). The presence or absence of T2-FLAIR mismatch sign was not associated with both PFS (46.8 months vs. 33.6 months, p=0.2526) and OS (not reached vs. 152 months, p=0.2087). Positive super T2-FLAIR mismatch sign cases have propensity to show longer PFS (112.7 months vs. 36.0 months, p=0.0710), and significantly longer OS (not reached vs. 152 months, p=0.0392). When super T2-FLAIR mismatch sign-positive cases were compared to negative cases in patients who did not accomplish entire removal, the PFS was significantly longer (p=0.0045) and there was a propensity for a longer OS (p=0.0543). CONCLUSIONS Super T2-FLAIR mismatch sign can be considered as a prognostic imaging biomarker for non-enhanced astrocytoma, IDH-mutant.
QOL-19. TUMOR TREATING FIELDS (TTFIELDS) THERAPY IN GLIOBLASTOMA (GBM): RELATIONSHIP BETWEEN PATIENT EXPERIENCE, GLOBAL REGION, AND AGE
Authors: Shermona Shockley, P Gage Gwyn, Renae Adams, Eleni Batzianouli, Heather Johnson, Huda Ismail Abdullah
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND TTFields therapy is a noninvasive, locoregional anticancer treatment approved for newly diagnosed and recurrent GBM based on efficacy and safety results in 2 global, randomized pivotal studies, supported by real-world evidence. METHODS In 2022, 2 questionnaires (mail or online) surveyed the real-world experiences of patients with GBM receiving TTFields therapy (NovoTTF-200A; Novocure®, GmBH) and their caregivers in Germany, Austria, and Switzerland (DACH), and the USA. RESULTS 545/1197 surveys were returned in DACH (46%); 1332/5031 in the USA (26%). Most respondents indicated satisfaction/high satisfaction with TTFields (in patients starting therapy, 82% [DACH] and 58% [USA]; in patients with &amp;gt;6 months use, 67% [DACH] and 72% [USA]). The following data pertain to patients with &amp;gt;6 months of TTFields use (n = 114 DACH; n = 375 USA). 63% in DACH reported that daily life was changed “much”/“very much”, and 35% “hardly at all”; in the USA, 17% indicated they were able to live as they did before therapy, 61% had to make adjustments but had returned to a normal routine, and 23% said therapy had markedly impacted daily life. 74% (DACH) and 73% (USA) would recommend to other patients. Common reasons for low satisfaction included skin irritation and device handling. To assess any impact of age, responses from patients aged ≥70 years ( &amp;gt;6 months use) from the USA (n = 82 [22%]) were analyzed (there were not enough elderly patients with &amp;gt;6 months use in DACH [n = 8] to analyze). As with the overall population, elderly patients in the USA reported they were satisfied/very satisfied (67%). 66% of elderly patients (USA) were very likely to recommend TTFields to someone else. CONCLUSIONS Surveys of patient/caregivers in DACH and the USA who used TTFields for GBM identified a high degree of satisfaction, including elderly patients. Most respondents would recommend TTFields to others.
QOL-06. HEALTH RELATED QUALITY OF LIFE INFLUENCES ON OVERALL SURVIVAL IN GLIOBLASTOMAS
Authors: Riho Nakajima, Masashi Kinoshita, Hirokazu Okita, Mitsutoshi Nakada
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Currently, in treatment of glioblastomas (GBM), emphasis is placed not only on prolonging prognosis but also on maintaining quality of life (QOL). The purpose of this study was to investigate the relationship between health related QOL and prognosis in GBMs and to examine factors that influence on QOL. Method: Participants were 34 patients with GBMs who underwent surgery (mean age, 56.4 years). All patients assessed Karnofsky performance status (KPS), several kinds of neurological and neuropsychological functions, and SF-36 for QOL. In SF-36, we calculated three summary component scores: physical, mental, and role/social component score (PCS, MCS, RCS, respectively). Cox-regression analysis was used to analyze relationship between QOL and progression-free survival (PFS) and overall survival (OS). To examine clinical and functional factors and brain regions associated with QOL, multiple regression analysis and the Voxel-based lesion symptom mapping (VLSM) were utilized. Result: When association between PFS/OS and QOL (PCS, MCS, and RCS) were analyzed, significant correlation was found only between OS and PCS (p = 0.039). Then, we investigated factors influencing on PCS. Using univariate analysis, the clinical factors associated with PCS were lesion location and KPS at 6 months (p = 0.037, p = 0.030, respectively). As for brain functions, visuospatial cognition and paralysis were significantly associated with PCS (p = 0.012 and p = 0.0056, respectively). Among these significant factors in univariate analyses, only visuospatial cognition and paralysis were associate with PCS via multiple regression analysis. Result of VLSM revealed that patients who resected the right medial superior frontal gyrus and deep part of the middle frontal gyrus showed significantly low PCS. Patients with VLSM positive region resected were more likely to have paresis and/or visuospatial cognitive deficit (p = 0.0013). CONCLUSION Health related QOL was associated with OS in GBMs. Factors influencing on QOL were visuospatial cognition and paresis, that may cause by lesion of the right frontal lobe.
QOL-22. USE OF TUMOR TREATING FIELDS THERAPY WITH ADJUVANT TEMOZOLOMIDE AND IMMUNOTHERAPY FOR NEW DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Samantha Cheng, Adilia Hormigo
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Treatment options for GBM remain limited, and novel approaches are required. One of them, Tumor Treating Fields (TTFields) therapy, is a non-invasive treatment modality that delivers low intensity, intermediate frequency, alternating electrical fields and increases survival through multiple mechanisms, including disrupting cell mitosis, triggering tumor cell death, and expanding CD8+ cytotoxic lymphocytes. METHODS In this prospective study, adult patients with ndGBM underwent standard-of-care treatment with maximal resection, followed by radiotherapy and temozolomide. Use of TTFields therapy, with a recommended daily use of ≥ 18 hours/day, throughout adjuvant temozolomide treatment and with immunotherapy, was investigated. RESULTS Eight patients received TTFields therapy. Use of TTFields was 2, 5, 6, 6, 8, 8, 10, and 16 months with an average of 10.2 months. The patient with the lowest use developed a grade 1 papulopustular scalp rash and discontinued use. Monthly average daily use ranged from 0% to 87%. Average daily use over treatment was 39%, 47%, 48%, 53%, 67%, 69%, 78%, and 83%. None of the patients achieved the goal for daily use every month. Four patients had a daily use ≥ 80% for at least one month of treatment. Except for one patient, whose daily use increased from 72% in the first month to 79% in the last month, all other patients down-trended in TTFields use. Six patients completed EORTC-QLQ-C30 surveys throughout the study. 3/8 had an overall increase in their global quality of life scale, 3 patients had a decrease, and 2 patients did not complete the survey. DISCUSSION In this study, the use of TTFields was suboptimal. We presume that with multiple treatments in the adjuvant phase including 6 cycles of temozolomide and optional TTFields use, patients did not recognize the potential therapeutic benefit of continued TTField therapy use and opted to remain only in the immunotherapy treatment.
RADT-05. SINGLE VERSUS MULTI-FRACTION STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: RATES OF LOCAL PROGRESSION AND NECROSIS
Authors: Kelsey Frechette, Leier Sara, Harmsen William, Nadia Laack, Anita Mahajan, Elizabeth Yan, David Routman, Merrell Kenneth, John Lucido, Michael Grams, Jay Brooks, Ian Parney, Bruce Pollock, Terry Burns, Ugur Sener, Paul Brown, William Breen
Journal: Neuro-Oncology (2023)

Abstract PURPOSE For large brain metastases, it is unknown whether single fraction stereotactic radiosurgery (sSRS) or multi-fraction stereotactic radiosurgery (fSRS) is optimal. We aimed to compare rates of local progression and necrosis between sSRS and fSRS for large brain metastases. METHODS Patients with intact or resected brain metastases with a target volume ≥ 4.2 cc (corresponding to a diameter ≥ 2 cm) treated with Gamma Knife (GK) or linear accelerator-based SRS from 2014-2022 were included in this retrospective review. RESULTS A total of 343 large brain metastases in 276 patients were included; 171 lesions were treated with sSRS (96% with GK) and 172 lesions with fSRS (100% with linear accelerator). Median lesion volume was 19.8 cc and 8.4 cc for fSRS and sSRS, respectively. Resection was performed prior to SRS in 228 (66%), with the remaining 115 metastases treated intact. There was no difference in rate of local progression between sSRS versus fSRS, or between resected versus intact targets (p &amp;gt;0.8 for both). Cumulative incidence of local progression (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 24% and 30%, respectively, compared to 22% and 34% for fSRS. FSRS was associated with significantly higher rates of necrosis than sSRS (HR 5.58, 2.38-13.08, p &amp;lt; 0.001). This association remained significant after controlling for target volume. Cumulative incidence of necrosis (with death as a competing risk) at 1 and 3 years for patients receiving sSRS was 1% and 3%, respectively, compared to 10% and 18% for fSRS. Necrosis rates were significantly higher with fSRS for both intact and resected targets (P &amp;lt; 0.02 for both). CONCLUSION While local control for large resected or intact brain metastases appears similar after sSRS or fSRS, this retrospective study shows higher rates of necrosis after fSRS. Prospective validation is needed.